Prostate Cancer Armamentarium Expanding

Oliver Sartor, MD

Men with prostate cancer now have an array of treatments, which was not the case a decade ago. The radiopharmaceutical radium-223 will probably be approved by the FDA for metastatic castration-resistant prostate cancer (CRPC). That likely approval is based on the overwhelmingly positive findings in the Alpharadin in the Treatment of Patients With Symptomatic Prostate Cancer (ALSYMPCA) trial. Another experimental agent, XL-184 (cabozantinib), has shown encouraging results in disease stabilization in men with metastatic CRPC and significant effects on bone scans. A third agent undergoing clinical trials is a neutraceutical, pomegranate extract, which appears to slow prostate-specific antigen (PSA) doubling time in men with rising PSA levels, but it is not clear if that will translate to improved outcomes. These prostate cancer treatments were discussed by different speakers at the 2011 Chemotherapy Foundation Symposium.

“Radium-223 promises to become a new standard of treatment for men with CRPC who have bone metastasis,” said Oliver Sartor, MD, director of the Tulane Cancer Center in New Orleans, Louisianna. This radiopharmaceutical is not only effective in improving survival, but its safety profile is at least as benign as placebo, according to results of the phase III, multicenter, randomized, placebo-controlled ALSYMPCA trial. Results of this trial were reported at the September 2011 meeting of the European Multidisciplinary Cancer Congress in Stockholm, Sweden.

The study included 922 patients with CRPC and at least 2 bone metastases and no known visceral metastasis who were randomized to radium-223 or placebo. At a pre-planned interim analysis, radium-223 had a clear survival benefit. Median overall survival was 14 months for radium-223 versus 11.2 months for placebo. The study was halted, and men in the placebo group were allowed to cross over to radium-223. Radium-223 also reduced the risk of time to first skeletal-related event by 39%. All subgroups benefited from this approach, including those who received prior docetaxel treatment. Amazingly, the placebo-treated patients had more side effects and a higher number of patients who discontinued treatment.

“We now have a variety of agents [for CRPC] that prolong survival. In the future we will need to learn how to combine them and sequence them,” Sartor said.

XL-184 (cabozantinib) is a dual inhibitor of mesenchymal epithelial transition factor (MET), a proto-oncogenic receptor, and vascular endothelial growth factor receptor 2. Theoretically, cabozantinib may block osteolytic lesions, said David C. Smith, MD, professor of the Department of Urology at the University of Michigan, Ann Arbor.

A phase II, randomized, discontinuation trial of cabozantinib versus placebo was conducted in 171 men with metastatic CRPC with measurable disease and evidence of disease progression. Median age was 68 years; 54% had bone pain, and 42% were taking narcotics for their pain. About 40% were pretreated with docetaxel. Results were good, so randomization to placebo was discontinued.

After 12 weeks of treatment, 68% had disease control (complete response, partial response, and stable disease). “Almost every patient had some evidence of activity [of the drug] on bone scan,” Smith said.

The major toxicities were fatigue (63%), thrombocytopenia (8%), and gastrointestinal perforation (1%). Fifty percent of patients required dose reductions. No significant effect was observed in patients who received prior docetaxel.

The moderator of the session, William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at the Mount Sinai School of Medicine in New York City, said that both radium-223 and cabozantinib target the microenvironment. “Radium-223 will be transformative, because of its efficacy and favorable toxicity. Cabozantinib should also be transformative. It had a remarkable effect on bone scans, but we need to see more studies,” Oh stated.

A randomized, phase II study of 2 different dose levels of pomegranate extract showed that the extract, which is more potent than pomegranate juice, increased the PSA doubling time by about 6.6 months, from 11.9 months at baseline to 18.5 months after 6 months of treatment (P < .001). No dose response was observed. The study included 104 patients with a rising PSA without evidence of metastasis; at baseline, median age was 72, median Gleason score was 6-7 (44% were

Three-quarters of patients with a PSA doubling time <3 months moved to a higher doubling time after taking pomegranate extract.

“The study met its primary endpoint but we did not see a dose response. Pomegranate extract may play a role in the treatment of older men who are looking for alternative therapies. I don’t recommend it to my patients, but if a patient of mine wants to take it and defer hormonal therapy, I tell him that the extract is safe,” stated lead author Michael A. Carducci, MD, professor of Urologic Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.